ANTI EPILEPTIC DRUGS pdf - د. نصير

Sunday 15 / 2 / 2015

©Ali Kareem 2014-2015

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ANTI-EPILEPTIC DRUGS

Lecture 5

Total lectures NO. 35

Dr. Naseer Al-Harchan

ANTI-EPILEPTIC DRUGS

Introduction

Seizure

• Seizures are sudden, transitory, and uncontrolled episodes of

brain dysfunction resulting from abnormal discharge of neuronal
cells with associated motor, sensory or behavioral changes.

Epilepsy

• A group of chronic CNS disorders characterized by recurrent

seizures.

Classification of Epileptic Seizures

I. Partial (focal) Seizures

A. Simple Partial Seizures

B. Complex Partial Seizures

C. Partial with secondary generalized tonic classic seizure

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures

B. Absence Seizures

C. Myoclonic Seizures

Pathological Basis

 Abnormal electrical discharge in the brain

 Coordinated activity among neurons depends on a controlled

balance between excitation and inhibition

 Any local imbalance will lead to a seizure

 Imbalances occur between glutamate-mediated excitatory

neurotransmission and gamma-aminobutyric acid (GABA)
mediated inhibitory neurotransmission

 Generalised epilepsy is characterised by disruption of large scale

neuro-networks in the higher centres.

Strategies in Treatment

• Stabilize membrane and prevent depolarization by action on ion

channels

• Increase GABAergic transmission

• Decrease EAA (Excitatory Amino Acid) Transmission

Classification of Anticonvulsants

Classical

• Phenytoin

• Phenobarbital

• Primidone

• Carbamazepine

• Ethosuximide

• Valproic Acid

• Trimethadione

Newer

• Lamotrigine

• Felbamate

• Topiramate

• Gabapentin

• Tiagabine

• Vigabatrin

• Oxycarbazepine

• Levetiracetam

• Fosphenytoin

• Others

Phenytoin

• Limited water solubility – not given i.m.

• Slow, incomplete and variable absorption.

• Extensive binding to plasma protein.

• Metabolized by hepatic ER by hydroxylation. Chance for drug

interactions.

• Therapeutic plasma concentration: 10-20 µg/ml

• Shift from first to zero order elimination within therapeutic

concentration range.

Phenytoin – Toxicity and Adverse Events

Acute Toxicity

• High i.v. rate: cardiac arrhythmias ± hypotension; CNS depression.

• Acute oral overdose: cerebellar and vestibular symptoms and

signs:

nystagmus, ataxia, diplopia vertigo.

Chronic Toxicity

• Dose related vestibular/cerebellar effects

• Behavioral changes

• Gingival Hyperplasia

• GI Disturbances

• Sexual-Endocrine Effects:

– Osteomalacia

– Hirsutism

– Hyperglycemia

Chronic Toxicity

• Folate Deficiency - megaloblastic anemia

• Hypoprothrombinemia and hemorrhage in newborns

• Hypersenstivity Reactions – could be severe. SLE, fatal hepatic

necrosis, Stevens-Johnson syndrome.

• Pseudolymphoma syndrome

• Teratogenic

• Drug Interactions: decrease (cimetidine, isoniazid) or increase

(phenobarbital, other AED’s) rate of metabolism; competition for
protein binding sites.

Carbamazepine (Tegretol)

• Second - most commonly prescribed anticonvulsant

• Structurally related to tricyclic antidepressants

• Uses:

– partial and tonic-clonic seizures

– neuropathic pain management

– Schizophrenia, bipolar disorder

• May be used in combination with Dilantin or Phenobarbital

 All types except absence seizures; particularly useful for

generalized tonic-clonic, simple and complex partial

 Inhibition of voltage-gated Na

channels

 Oral, slow and erratic, 75% plasma protein bound; t

1/2

=36 hrs

initially, decreasing to 20 hrs following continuous therapy
(autoinduction), active metabolite excreted

 Diplopia and ataxia, GI upset, hypersensitivity, serious toxicity

including aplastic anemia, agranulocytosis

 Drug interactions are many, related to the hepatic enzyme

inducing properties of carbamazepine

• Toxicity similar to phenytoin

Adverse effects

– CNS:

• Restlessness, irritability, agitation

• Dizziness, confusion, ataxia, encephalopathy

– Renal

• Renal failure, urinary frequency

• Water retention (stimulates ADH)

– Visual changes

• Agranulocytosis

• Lupus

• Arrhythmia & cardiac conduction abnormalities

• Toxicity: bone marrow depression, hepatic dysfunction, visual

changes

• Numerous drug interactions

• Erratically absorbed, better absorption on full stomach

Phenobarbital

• The only barbiturate with selective anticonvulsant effect.

• Bind at allosteric site on GABA receptor and ↑ duration of

opening of Cl channel.

• ↓ Ca-dependent release of neurotransmitters at high doses.

• Inducer of microsomal enzymes – drug interactions.

• Toxic effects: sedation (early; tolerance develops); nystagmus &

ataxia at higher dose; osteomalacia, folate deficiency and vit. K
deficiency.

• In children: paradoxical irritability, hyperactivity and behavioral

changes.

• Deoxybarbiturates: primidone: active but also converted to

phenobarbital. Some serious additional ADR’s: leukopenia, SLE-
like.

Valproic Acid

• Effective in multiple seizure types.

• Blocks Na and Ca channels. Inhibits GABA transaminase. Increases

GABA synthesis.

• Toxicity: most serious: fulminant hepatitis. More common if

antiepileptic polytherapy in children < 2 years old. (?) Toxic
metabolites involved.

• Drug interactions: inhibits phenobarbital and phenytoin

metabolism.

Ethosuximide

• Second - most commonly prescribed Drug of choice for Absence.

Blocks Ca++ currents (T-currents) in the thalamus.

• Not effective in other seizure types

• GI complaints most common

• CNS effects: drowsiness lethargy).

• Has dopamine antagonist activity (? In seizure control) but causes

Parkinsonian like symptoms.

• Potentially fatal bone marrow toxicity and skin reactions (both

rare)

Benzodiazepines

• Diazepam (Valium) IV, IM

• Lorazepam (Ativan) IV

– Used to terminate status epilepticus

– Close medical supervision & resuscitative equipment should

be available

 potentiates GABAA receptor function via a distinct allosteric

binding site on the protein termed the benzodiazepine receptor.
↑ frequency of opening of Cl channel.

 diazepam (i.v.)- drug of choice for the treatment of status

epilepticus

 clonazepam and clorazepate- long-term treatment of absence,

myoclonic, akinetic and atonic seizures; tolerance to
anticonvulsive action limits clinical usefulness of benzodiazepines

 potentiates GABA

receptor function via a distinct allosteric

binding site on the protein termed the benzodiazepine receptor

 oral, t

1/2

: clonazepam=1 day; clorazepate=2 hrs; i.v. diazepam=1-2

days); very high plasma protein binding, N-desmethyldiazepam
(t

1/2

=3 days) is active metabolite of diazepam and clorazepate,

clonazepam is primarily reduced to inactive metabolites

 sedation, ataxia; hyperactivity and irritability in children; high

therapeutic index, low incidence of toxicity

 additive or synergistic effects with other sedative hypnotics

Enhancers of GABA Transmission

• Gabapentin: Developed as GABA analogue. Mechanism: Increases

release of GABA by unknown mechanism.

• Vigabatrin: Irreversible inhibitor of GABA transaminase. Potential

to cause psychiatric disorders (depression and psychosis).

• Tiagabine: decreases GABA uptake by neuronal and extraneuronal

tissues.

Done by

Ali Kareem